GnomCmp: A Quantitative Approach for Comparative Analysis of Closely Related Genomes of Bacterial Pathogens

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Comparative genome analysis is a powerful approach to understanding the biology of infectious bacterial pathogens. In this study, a quantitative approach, referred to as GnomCmp, was developed to study the microevolution of bacterial pathogens. Although much more time-consuming than existing tools, this procedure provides a much higher resolution. GnomCmp accomplishes this by establishing genome-wide heterogeneity genotypes, which are then quantified and comparatively analyzed. The heterogeneity genotypes are defined as chromosomal base positions that have multiple variants within particular genomes, resulted from DNA duplications and subsequent mutations. To prove the concept, the procedure was applied on the genomes of 15 Staphylococcus aureus strains, focusing extensively on two pairs of hVISA/VISA strains. hVISA refers to heteroresistant vancomycin-intermediate S. aureus strains and VISA is their VISA mutants. hVISA/VISA displays some remarkable properties. hVISA is susceptible to vancomycin, but VISA mutants emerge soon after a short period of vancomycin therapy, therefore making the pathogen a great model organism for fast-evolving bacterial pathogens. The analysis indicated that GnomCmp could reveal variants within the genomes, which can be analyzed within the global genome context. GnomCmp discovered evolutionary hotspots and their dynamics among many closely related, even isogenic genomes. The analysis thus allows the exploration of the molecular mechanisms behind hVISA/VISA evolution, providing a working hypotheses for experimental testing and validation.